1. Field of the Invention
This invention relates generally to the prevention of solar radiation absorption-induced skin lipid degradation resulting in the formation of carcinogenic products, particularly malonaldehyde, and more particularly relates to a protective composition having ideal properties for such purpose.
2. Description of the Prior Art
Repeated exposure to solar or ultraviolet radiation of lightly pigmented individuals may result in actinic skin--a dry, brown, inelastic, wrinkled skin. Although cosmetically undesirable, actinic skin is not harmful in itself, but is a warning that such conditions as senile keratosis, squamous cell epithelioma, and basal cell epithelioma may develop.
Chronic solar or ultraviolet radiation exposure results in a number of changes in the skin including wrinkling, atrophy, hyper- and hypopigmented macules, telangiectasia, yellow papule and plaque formation, and actinic keratosis. The action spectrum for the induction of some of these conditions in experimental animals by ultraviolet radiation is the same as the action spectrum primarily responsible for solar-induced erythema or sunburn in humans, between 290-320 nm. Some reports indicate that the longer ultraviolet wavelengths between 320-400 nm accentuate the early toxic response to the shorter ultraviolet wavelengths; a mild erythema in humans can also be produced by such radiation.
The role of ultraviolet radiation as a constituent of sunlight in the development of the common human skin cancers, i.e., the basal cell epithelioma, the squamous cell carcinoma, and the much less common malignant melanoma, have been supported by astute observations and epidemiological studies. These various skin cancers are extremely common in susceptible individuals; about 300,000 new cases of skin cancer occur each year. However, investigations confirming this association, as well as the determination of the action spectrum and the required energy levels, have been confined to the aforementioned animal experimentation for practical and ethical reasons.
In addition to animal experimentation, a considerable body of circumstantial evidence supporting the role of ultraviolet radiation, particularly in the form of sunlight, in these three types of skin cancer has been gathered and can be summarized as follows:
(a) Skin cancers do occur predominantly on the sun exposed parts of the body PA1 (b) They are more common in regions of the world that receive the most sunlight PA1 (c) Pigmented races are much less susceptible to skin cancer formation than Caucasians who work outdoors.
However, the morphological distribution of the most common cutaneous cancer, the basal cell epithelioma, indicates that factors other than ultraviolet radiation must play a role. About one-third of basal cell epitheliomas occur on areas of the skin receiving minimal sun exposure. Therefore, though ultraviolet radiation appears to be a dominant factor in this tumor formation, undetermined factors must participate.
Further, the nature of the chromophore in the skin which absorbs ultraviolet light energy and initiates pathological responses, including erythema, is not known. Proteins containing aromatic amino acids and nucleic acids have been considered likely candidates because of their absorption spectra and the profound effect of ultraviolet energy on these molecules. However, a number of other substances including urocanic acid, melanin, and unsaturated fatty acids of phospholipids have been speculated upon as playing a role in the initial absorption of light energy. It appears as though multiple chromophores are involved in a complex process. Whether this ultraviolet energy absorption leads to the formation of carcinogenic substances has heretofore been the subject of great controversy.
The only practical technique for reducing the pathological effect of ultraviolet radiation in the form of sunlight upon the skin would appear to be to reduce the exposure of skin to solar radiation. This may be accomplished by avoiding exposure of the individual to sunlight. Such limitations do not, however, fit the designs of a civilization which enjoys, or must participate in, outdoor activity, and which further admires melanization of the skin through insolation.
Classically, avoidance of sun exposure did not appear necessary because the effects of sun exposure appeared to be readily mitigated by the topical application of an ultraviolet screening agent. These agents effectively mitigate erythema; no reports are known which indicate how effectively they reduce the other pathological effects of solar radiation in humans. That the known ultraviolet screening products provide such further protection against other non-erythematic effects has recently been assumed by the U.S. Food and Drug Administration, which now allows sellers of consumer sunscreen products to advertise use of their products as a method that "may help prevent premature aging and wrinkling of the skin and skin cancer due to sun overexposure." No experimental verification or other proof of such efficacy in reducing skin cancer has been forthcoming for the extant commercial preparations.
The FDA currently has listed twenty-one dermatologically acceptable sunscreens, which include individual species or mixtures of salicylates, para-aminobenzoates, cinnamates, acid-esterified gallates, napthoates and benzophenones heretofore known to the art, which may be utilized in consumer sunscreen products. Commercial preparations commonly contain these sunscreen compounds together with a cosmetically acceptable carrier and a stabilizer material, e.g., an antioxidant, to protect the oxygen-liable fat and oil ingredients of the preparation, which may include both the sunscreen compounds themselves and components of the carrier material.
Antioxidants or oxidation inhibitor compounds must be used in restricted concentrations to accomplish stabilization of these components against oxidation. This restricted concentration range within which these compounds control or inhibit oxidation is referred to as the antioxidant concentration range and is based on concentration of antioxidant to the fat and oil components; these concentrations are well known to the art. See DeNavarre, The Chemistry and Manufacture of Cosmetics, Van Nostrand Company, Inc. (1962), p. 310.
Increasing the amount of oxidation inhibitor compound or antioxidant beyond these values may result in no additional or decreased protection of the oxygen-liable materials. In fact, these compounds actually demonstrate a pro-oxidant effect when used in excess of their antioxidant-effective concentration range. These materials, when present in a pro-oxidant concentration, can be said to be latent oxidation inhibitor compounds. This marked pro-oxidative effect is especially demonstrated by phenolic substituent-bearing latent oxidative inhibitor compounds, including nordihydroguaiaretic acid (NDGA), alcoholic esters of gallic acid, such as propyl gallate, and the pure or mixed alpha, beta, gamma, delta, epsilon, zeta and eta tocopherols.
There is then an art recognized incentive for adding oxidation inhibitor compounds to sunscreen preparations containing the known, FDA approved ultraviolet absorbing compounds only in concentrations within the antioxidant concentration range. The maximum required concentration for phenolic antioxidants in the antioxidant range is about 0.1 wt % based on the fat and oil components of the preparation. For sunscreen preparations containing an evaporative carrier vehicle such as water or alcohols, the fat and oil component content would not exceed about 50 wt % of the preparation. The maximum required phenolic antioxidant concentration based on total product composition therefore would not exceed about 0.05 wt %. For sunscreen preparations that are entirely composed of fatty and oily type materials, the maximum required phenolic antioxidant concentration based on total product composition would not exceed about 0.1 wt %.
In practice, commercial sunscreen preparations generally contain about one-half or less of the maximum useful phenolic antioxidant concentration.
Solar light is an accelerator of oxidation. As consumer sunscreen preparations are frequently exposed to solar radiation prior to application to the skin to control erythema, these preparations are stored in colored containers and wrappers which absorb such radiation. No teachings are extant directed to the use of oxidation inhibitor compounds to stabilize the oxygen-liable materials in these preparations against the effects of ultraviolet light.
Similar teachings are found in the medical and cosmetic arts respecting protection of living human skin from ultraviolet radiation. The application of ultraviolet absorbers or reflectors to the skin during sun exposure is the only recognized technique of protecting that organ from the pathological effect of sunlight. The use of oxidation inhibitor compounds for that purpose has never been taught, and, as noted above, commercial products applied to skin have contained only trace amounts of antioxidants, with but one class of exceptions.
The exception is when the oxidation inhibitor compound also has ultraviolet-absorbing or sunscreen properties. Some phenolic and quinone antioxidants such as hydroquinone and certain gallates have sunscreen properties, and have been employed in commercial sunscreens in concentrations of greater than at least 4% by weight of the total product, a concentration that would result in a minimum acceptable sunscreen effect, i.e., at least an 85% absorption of erythemal ultraviolet light. These products were withdrawn from the market, however, for it was found that the sunscreen-effective concentration was dermatologically unacceptable. For instance, it was shown that three of twelve subjects treated with a hydroquinone sunscreen preparation developed atypical dermatoses, including erythema, dermatitis, and several systemic effects The gallates were similarly shown to be skin irritants.
Similar results leading to withdrawal of other commercial, non-sunscreen cosmetic products utilizing compounds having antioxidant/oxidation inhibitor properties were noted for the tocopherols, such as the Mennen E deodorant products. See Consumer Reports, May 1973, pp. 352-53; June 1973, p 371.
These problems were overcome by acid esterification of the phenolic hydroxy (--OH) groups. Such esterification, however, destroyed the antioxidant/oxidation inhibitor properties of these compounds, and, in the case of the tocopherols, destroyed whatever ultraviolet absorbing sunscreen properties demonstrated thereby at those concentrations, which effect was hitherto unknown and is discussed in my issued U.S. Pat. No. 4,144,325. Therefore, it has heretofore been recognized in the art that phenolic and quinone-type oxidation inhibitor compounds are dermatologically unsuitable for use in the concentrations required as the ultraviolet absorbing compound in sunscreen preparations.
No practical value or teaching of use is known, then, for phenolic types of oxiditive inhibitor compounds in sunscreen preparations between the pro-oxidant and sunscreen concentration levels, which correspond to between about 0.1 to 2 wt % of the composition containing said compounds.
Recent reports have been made in the literature about solar ultraviolet-induced lipid peroxidation. Pryor, Free Radicals in Biology, Academic Press (1977), pp. 116, 232. Sunlight has been reported to induce the presence of lipoperoxides on the skin, but the significance of the phenomenon has not been recognized. No known reports have been made describing lipid peroxidation of skin lipids treated with the known prior art ultraviolet absorbing sunscreen preparations.
Yet, I have surprisingly found that human skin exposed to solar radiation after treatment with topical applications of known prior art ultraviolet absorbing compound-containing sunscreen preparations, which also contain concentrations of oxidation inhibitor compounds/antioxidants in the antioxidant range, is subjected to skin lipid peroxidation which produces the carcinogenic and skin aging compound malonaldehyde: ##STR1## Malonaldehyde is a mutagen, as established by the Ames Salmonella test. Since about 90 per cent of the compounds found mutagenic in the Ames test are also carcinogenic, the probability of malonaldehyde being a human carcinogen is very great. Malignant skin tumors have been reported in rats receiving an effective topical application of 60 .mu.g of malonaldehyde; as a result, malonaldehyde is now considered a potent carcinogen by the scientific community. As it is a water soluble agent, its indigenous formation on and in the skin during sun exposure does not restrict its presence to the skin. It can enter and be carried by the vascular system to all parts of the body. What deleterious effects it has there are unknown, although it has recently been implicated in certain types of heart damage.
Malonaldehyde has also been shown to be a dangerous cross linking agent capable of in vivo cross linking with the primary amino groups of proteins, nucleic acids and their bases, or phospholipids. Cross linking of skin proteins, especially collagen, is widely thought to be a mechanism of both normal and premature skin aging.
The presence of malonaldehyde on the skin during sun exposure thus offers a plausible explanation for the etiology of both skin cancers and premature wrinkling and aging of the skin caused by excessive sun exposure.
Generally, all commercial sunscreen preparations which I have tested do not reduce solar radiation absorption-induced malonaldehyde formation from skin epithelial tissue more than about 50% of the concentration that would have developed in the absence of application of the sunscreen. The majority of the most effective sunscreens known to the art, even when combined with an antioxidant in the antioxidant range, reduce malonaldehyde by much less than 50% when applied to the skin exposed to sunlight.
More troubling is that my testing showed that use of several consumer sunscreen products actually increased the amount of malonaldehyde formed over that which would have developed in the absence of the sunscreen applied.
Since there is no known effect threshold value for human carcinogens, any concentration of a carcinogen in or on the body is dangerous. It is known that exposure to a higher concentration of a carcinogen is more dangerous than a lower concentration. Therefore, any reduction in exposure to a carcinogen, especially reduction to zero or near zero exposure, is highly desirable.
None of the known, most widely used and effective ultraviolet absorbing compound-containing sunscreens known to the art, e.g., those containing salicylates, para-aminobenzoates, cinnamates, acid-esterified gallates, napthoates and benzophenones, therefore, provide the critical property of preventing pathological and carcinogenic chemicals such as malonaldehyde from forming on the skin during exposure to solar radiation while reducing erythema.